EP2765991A1 - In-situ-formendes hydrogel und verfahren zu seiner verwendung - Google Patents

In-situ-formendes hydrogel und verfahren zu seiner verwendung

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Publication number
EP2765991A1
EP2765991A1 EP12840669.1A EP12840669A EP2765991A1 EP 2765991 A1 EP2765991 A1 EP 2765991A1 EP 12840669 A EP12840669 A EP 12840669A EP 2765991 A1 EP2765991 A1 EP 2765991A1
Authority
EP
European Patent Office
Prior art keywords
hydrogel
repeat units
polymer
hydrogei
lcst
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12840669.1A
Other languages
English (en)
French (fr)
Other versions
EP2765991A4 (de
Inventor
Derek OVERSTREET
Brent Vernon
Ryan MCLEMORE
Alex MCLAREN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Arizona
Arizona State University ASU
Original Assignee
University of Arizona
Arizona State University ASU
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Filing date
Publication date
Application filed by University of Arizona, Arizona State University ASU filed Critical University of Arizona
Publication of EP2765991A1 publication Critical patent/EP2765991A1/de
Publication of EP2765991A4 publication Critical patent/EP2765991A4/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/24—Materials or treatment for tissue regeneration for joint reconstruction

Definitions

  • shrinking is an important consideration. Usually, the ideal case is that the material transitions quickly from liquid to solid with almost no change in volume. Shrinking or swelling inherently causes changes in the hydrogel's mechanical properties, porosity, and size. Wound healing and embolization applications require retention of the hydrogel's original size at the injection site and good contact with the surrounding tissue. For controlled drug delivery, a fast sol-to-gel transition without syneresis could reduce the high initial burst release of hydrophilic drugs typical of many in situ forming materials. For successful use as synthetic extracellular matrices in vitro or in vivo, gels must retain a high volume fraction of water in order to support cell growth.
  • a hydrogel is presented.
  • An aqueous solution of a polymer comprises a first lower critical solution temperature (“LCST”).
  • LCST first lower critical solution temperature
  • the hydrogel is configured to be converted in vivo into a modified hydrogel comprising a modified polymer, wherein an aqueous solution of the modified polymer comprises a second lower critical solution temperature (“LCST”), and wherein the second LCST is greater than the first LCST.
  • Applicants' hydrogel provides an in situ-forming and degradable platform for the controlled local release of drugs when dissolved in physiological ly compatible aqueous solutions.
  • Applicants' hydrogel can be used as injectable or space-filling carriers for localized delivery of antibiotics or other drugs for treatment or prevention of orthopaedic infections such as in total hip arthroplasty.
  • Applicants' hydrogel can be administered to nearly any location in the body where a local pathology might arise. After gelation, the resulting gel begins to release one or more medicaments. The hydrogel can also be administered to some locations in the body for long-term systemic delivery. Eventually, all the entrapped one or more medicaments are released and the gel dissolves.
  • the various embodiments of Applicants' hydrogel comprise a polymer with a lower critical solution temperature (LCST) in aqueous solution that is less than body temperature.
  • LCST critical solution temperature
  • the polymer is soluble in water.
  • that aqueous polymer solution forms a soft and solid water-swollen hydrogel.
  • pendent ester groups hydrolyze to form a modified hydrogel, wherein the modified hydrogel comprises a higher LCST.
  • the modified hydrogel dissolves, leaves the site of administration, and is excreted from the body via the urine.
  • FIG. 1 graphically illustrates relative absorbance at 450 nm wavelength of 0.25 wt% solutions of Applicants' hydrogel I;
  • FIG. 2 shows a LCST of 5 wt% solutions of poly(NiPAAm-co-DBLA-co-JAAm) with 5.9 mol% DBLA, 2.3 moI% JAAm determined by cloud point as a function of time, wherein NIPAAm is N-isopropylacrylatnide, DBLA is (R)-a-Acryloyloxy- ⁇ , ⁇ -dimethyl-y-butyrolactone, and JAAm is Jeffaminc M-1000 acrylamide;
  • FIG. 3 shows deswe!ling of a control polymer 30 wt% poly(NIPAAm-co-DBLA) at various times after gelation in excess PBS (pH 7.4) at 37°C;
  • FIG. 4 shows swelling and degradation behavior of Applicants' terpolymer I based gel comprising poly(NlPAAm-co-DBLA-co-JAAm) in excess PBS (pi I 7.4);
  • FIG. 5 graphically illustrates the mass of vancomycin released from 1 ml. gels loaded with 50,000 micrograms vancomycin HCl and 1 niL bone cement samples loaded with 142,000 micrograms vancomycin HCl;
  • FIG. 6 graphically illustrates an amount of vancomycin released as a fraction of the drug loaded
  • FIG. 7 graphically illustrates a fraction of loaded vancomycin released from
  • FIG. 8 summarizes Applicants' method to deliver a medicament to an injection site within the body of an animal, including a human.
  • tissue repair such as tissue repair, embolization, and drug delivery.
  • Administering these materials by injection provides reduced infection risk, scar formation, and treatment cost relative to implantation.
  • In situ forming materials can provide local, controlled delivery of therapeutics directly to the desired area with reduced risk of side effects compared with commonly performed systemic delivery.
  • materials that form in situ are Ideal for use in spaces that
  • NIPAAm N- isopropylacrylamide
  • LCST critical solution temperature
  • poly(NIPAAm) As a solution of poly(NIPAAm) is heated above its LCST (near 32°C), polymer- polymer interactions between the hydrophobic isopropyl groups become more favorable than the polymer-water interactions with NIPAAm side group. Upon this transition, the polymer chains collapse to form a semisolid hydrogel at sufficiently high polymer concentrations for chain entanglement.
  • Various properties such as polymer LCST, chemical reactivity, sensitivity to various stimuli (pH, enzymes), or gel swelling can be controlled by incorporating small molar fractions ( ⁇ 10%) of comonomers with NIPAAm in order to provide a material for a particular application. For example, hydrophobic comonomers decrease the LCST while hydrophilic comonomers increase the LCST.
  • JEFFAMINE M- 1000 is a random copolymer of ethylene oxide (EO) and propylene oxide (PO) in a 19:3 EO:PO ratio with one terminal amine and one terminal methoxy group.
  • EO ethylene oxide
  • PO propylene oxide
  • Applicants' hydrogei represents a more clinically viable class of injectable materials for drug delivery by imparting swelling and drug release control via JEFFAMINE ⁇ - ⁇ 000 in a resorbable polymer.
  • Applicants' have further discovered that use of substituted aerylate comonomer (R )- (DBLA) increases the LCST of Applicants' hydrogei I as a result of a ring-opening mechanism which converts hydrogei I into a modified hydrogei and a provides an increased LCST without the loss of low molecular weight byproducts.
  • R aerylate comonomer
  • DBLA substituted aerylate comonomer
  • TAA total hip arthroplasty
  • the incidence of prosthetic joint infection in total hip and total knee arthroplasties is approximately 1.5-2.5% for primary interventions and higher for revision procedures performed secondary to infection. While the incidence of infection is relatively low, the high number of operations overall combined with the high cost of treating aninfected arthroplasty (over $50,000 in Year 1995 dollars) make this an area of great need.
  • R l and R2 are independently selected from the group consisting of H, alky 1, phenyl, benzyl, 2-cyanoprop-2-yl, 4-cyanopentanoic acid-4-yIethyl ⁇ 2-propionate, sulfate, 2- [2-methoxypropan-2-yl)oxy]propan-2-yl, and a dithioester derived from a RAFT chain transfer agent such as 4-cyano-4 ⁇ (ethylsulfanylthiocarbonyl)
  • pendent group R8 comprises a linkage with the polymer backbone selected from the group consisting of an ester, amide, thioaniide, thiourea, anhydride, thioester, thiourea, and alky i. In certain embodiments, pendent group R8 comprises at least one ester or anhydride.
  • linkage R8 is selected from the group consisting of ester, amide, thioamide, thiourea, anhydride, thioester, thiourea, and alkyi.
  • either linkage R8 or pendent group R6 comprises at least one ester or anhydride.
  • R6 is selected from the group consisting of alkyi. phenyl, polyesters, and lactones. In certain embodiments, R6 comprises a substituted butyroiactone.
  • R7 comprises an amide linkage.
  • R7 comprises a thioamide linkage. In certain embodiments, R7 comprises a urea linkage. In certain embodiments, R7 comprises a thiourea linkage. In certain embodiments, R7 comprises an ester linkage. In certain embodiments, R7 comprises an anhydride linkage.
  • the water soluble polymer comprises a polyether.
  • the water soluble polymer comprises polyether II formed by ring opening polymerization of ethylene oxide, wherei R9 is selected from the group consisting of H, methyl, methoxy, and hydroxy!.
  • n is between about 5 and about 2500.
  • the water soluble polymer comprises polyether III formed by ring opening polymerization of propylene oxide.
  • n is between about 15 and about 250.
  • the water soluble polymer comprises polyether IV formed by co-polymerization of ethylene oxide and propylene oxide.
  • r is between about 5 and about 2500, and p is between about 1 and about 1000.
  • the water soluble polymer comprises polyether V formed by ring opening polymerization of tetrahydrofuran.
  • n is between about 10 and about 50.
  • the water soluble polymer comprises a water-soluble
  • graft terpolymer I comprises a plurality of repeat units VI formed using monomer VII, a plurality of repeat units IX formed using monomer X, and a plurality of repeat units XI using monomer XII.
  • graft terpolymer I comprises a plurality of repeat units VI formed using monomer VII, a plurality of repeat units IX formed using monomer X, and a plurality of repeat units XIII using monomer XIV.
  • graft terpolymer I comprises a plurality of repeat units VI formed using monomer VII, a plurality of repeat units IX formed using monomer X, and a plurality of repeat units XV using monomer XVI.
  • graft terpolymer 1 comprises a plurality of repeat units VI formed using monomer VII, a plurality of repeat units IX formed using monomer X, and a lurality of repeat units XVI 1 using monomer XVIII.
  • graft terpolymer I comprises a plurality of repeat units VI formed using monomer VII, a plurality of repeat units IX formed using monomer X, and a plurality of repeat units XIX using monomer XX.
  • graft terpolymer I comprises a plurality of repeat units VI formed using monomer VII. a plurality of repeat units IX formed using monomer X, and a plurality of repeat units XXI using monomer XXII.
  • a is between about 10 and about 1000, b is between about 1 and about 250, and c is between about 1 and about 500,
  • Terpolymer I can be synthesized via a number of different procedures.
  • Applicants' graft terpolymer 1 can be prepared by free radical polymerization.
  • Graft terpolymer 1 can also be prepared by reversible addition-fragmention chain transfer (“RAFT”) polymerization.
  • RAFT reversible addition-fragmention chain transfer
  • RAFT agent thiocarbonylthio compounds
  • a free radical polymerization usually the same monomers, initiators, solvents and temperatures can be used.
  • RAFT concentration of the initiator is usually lower than in conventional radical polymerization.
  • Radical initiators such as azobisisobutyronitrile (A!BN) and 4,4'- Azobis(4-cyanovaleric acid) (ACVA) which is also called 4,4'-Azobis(4 ⁇ cyanopentanoic acid) are widely used as the initiator in RAFT.
  • A!BN azobisisobutyronitrile
  • ACVA 4,4'- Azobis(4-cyanovaleric acid)
  • RAFT 4,4'-Azobis(4 ⁇ cyanopentanoic acid
  • polymerization is known for its compatibility with a wide range of monomers, including for example acrylates and aery lam ides.
  • Graft terpolymer I as either a random copolymer or a block copolymer, can also be prepared by atom transfer radical polymerization ("ATRP").
  • ATRP atom transfer radical polymerization
  • NIPAAM N-isopropylacrylamide
  • ATRP atom transfer radical polymerization
  • ECP ethyl 2-chloropropionate
  • Me 6 TRE CuCI/tris(2- dimethylaminoethyl)amine
  • An embodiment of Applicant's hvdrogel I comprises a random terpolymer formed using three monomers, namely N-isopropylacrylamide (NIPAAm), JEFFAMiNE M-1000 acrylamide (JAAm), and acryloySoxy-p.p-dimemyi-y-butyrolactone (DBLA).
  • NIPAAm N-isopropylacrylamide
  • JAAm JEFFAMiNE M-1000 acrylamide
  • DBLA acryloySoxy-p.p-dimemyi-y-butyrolactone
  • NIPAAm monomer was recrystallized from hexane.
  • Azobisisobutyronitnle (AIBN) was recrystallized from methanol.
  • HPLC grade tetrahydrofuran (THF) was used for low molecular weight polymerizations and as the mobile phase for molecular weight and po!ydispersity determination.
  • JEFFAMINE M-1000 polyetheramine was donated by Huntsman Corporation (The Woodlands, TX, USA).
  • JEFFAMINE M-1000 acr lamide was synthesized from JEFFAMINE M- 1000 polyetheramine by aery loy ration with acryloyl chloride.
  • JEFFAMINE M-1000 (20 g, 20 mmo!) was dissolved at 10 w/v% in dichloromethane (DCM) along with triethyiamine (3.3 mL, 24 mmol) and maintained at 0°C under nitrogen atmosphere.
  • DCM dichloromethane
  • triethyiamine 3.3 mL, 24 mmol
  • Acryloyl chloride (1.95 mL, 24 mmol) was then added dropwise into the solution under stirring and the reaction was allowed to proceed for 1 hour at 0°C and then at room temperature for at least 5 hours under nitrogen atmosphere.
  • Hydrogel I prepared using NIPAAm, DBL, and JAAm were synthesized by radical polymerization with 80% dioxane / 20% THF as the solvent, but other solvents may be used, including methanol, ethanol, water, benzene, acetone, isopropano!, pure dioxane, pure tetrahydrofuran, or others. All three monomers (NIPAAm, DBLA, and JAAm) were dissolved in the solvent. Monomer solution (10 w/v%) was bubbled with nitrogen for at least 10 minutes prior to addition of initiator to reduce dissolved oxygen. After this time, AIBN (initiator) was added (-0.007 mol AIBN/mol of total monomer) and the reaction allowed to proceed for 24 hr at 65°C under a slight positive pressure of nitrogen.
  • Applicants' hydrogel was collected by precipitation into 10 to 15-fold excess of a solvent in which the polymer is not soluble, such as chilled diethyl ether or hexane. Following precipitation, the product was collected by filtration and dried overnight under vacuum. The product was then dissolved in deionized water and can optionally be dialyzed against 3500 MWCO at 4°C for 20 hours with the excess
  • the materials can be sterilized (such as by ethylene oxide gas sterilization) and then dissolved in 150 raM phosphate buffered saline (pH 7.4). After dissolution of the polymer, drug powder (finely ground) is added directly to the polymer solution and vortex mixed to distribute the drug evenly throughout the solution.
  • the solutions can be stored in a freezer until use and thawed at the time of use. The solution then can be injected, brushed, poured, sprayed, or otherwise administered as a liquid at the desired site. The solution can also be allowed to warm to above its initial LCST and then implanted as a soft hydrogel at the desired site.
  • desired sites for delivery of this material might include the surface of a joint prosthesis, the intramedullary canal before implantation of a prosthesis, an infected area, or any location deemed to have a risk of future infection.
  • An example formulation might be a 30 wt% polymer solution with approximately 50 mg vancomycin hydrochloride loaded per mL of polymer solution.
  • Hydrogels are defined as three-dimensional (3D), water-swollen polymer networks formed as a result of physical or chemical cross-linking. Because of their high water content and mechanical resemblance to natural tissues, hydrogels show promising biocompatibility and potential for medical applications. Injectable hydrogel formulations are especially attractive due to their minimally invasive delivery procedure, providing reduced healing time, reduced scarring, decreased risk of infection, and ease of delivery compared with surgically implanted materials.
  • Polymeric hydrogels which undergo cross) inking during or after administration to a joint space may represent an improvement because such hydrogels undergoes an increase in viscosity within thejoint space following administration.
  • the hydrogel precursor may be administered as a relatively less viscous liquid, then
  • Some in situ crosslinking hydrogels are viseoelastic, providing properties that can allow for the gel to remain intact within the joint by yielding during joint motion, conforming to the shape of the joint space in a ay that is analogous to a highly viscous liquid. Because of their theological properties, viseoelastic hydrogels are especially well-suited to conform to the surface of a prosthetic joint (or other surfaces present in a joint) to provide effective and sustained local concentrations of drug within the joint. In certain embodiments. Applicants utilize a crossiinked hydrogel injected into a joint space.
  • crossiinked hydrogel Applicants mean a physically or chemically crossiinked polymer-containing material containing over 50 weight percent of an aqueous solvent.
  • the ge! is crossiinked prior to injection.
  • the gel is crossiinked a ter injection in the joint space.
  • Appl icants' method administers a hydrogel in vivo to a joint space of an animal.
  • the hydrogel forms by physical crosslinking (for example, by heating above an LCST).
  • the crossiinked hydrogel forms by supramoiecular self-assembly.
  • the crossiinked hydrogel forms by covalent crosslinking.
  • the crossiinked hydrogel is administered by transcutaneous injection. In certain embodiments, the crossiinked hydrogel is administered to the joint space during a surgical procedure.
  • the crossiinked hydrogel contains no medicament. In certain embodiments, the crossiinked hydrogel comprises a medicament. In certain embodiments, the medicament comprises an antimicrobial.
  • the crossiinked hydrogel is administered to the hip joint in conjunction with total hip arthroplasty. In certain embodiments, the crossiinked hydrogel is administered to the knee joint in conjunction with total knee
  • the joint space is the hip joint. In certain embodiments, the joint space is the knee joint.
  • injected hydrogel I. in solution becomes a soft semi-solid filler which steadily delivers antibiotics directly at the surface of the implant which may do so without disrupting the fit between the bone and the prosthesis or generating wear debris from joint motion.
  • the drug concentration near the implant can be maintained at a high level in order to prevent infection, while the systemic exposure to the drug (and the corresponding side effects) can remain low.
  • PMMA poly(methyl methacrylate)
  • the drug(s) antibiotics or antifungals
  • the drug(s) are finely ground and mixed into the cement before implantation.
  • Local delivery of drugs drug (drugs administered near the implant site) is required in order to provide high drug concentration at the desired site with low concentration elsewhere in the body.
  • Systemic administration (such as by intravenous infusion) does not effectively target the implant surface and can cause toxicity and side effects at a dose that would be therapeutic at the implant surface.
  • the drug release is inefficient, meaning that a low fraction ( ⁇ 10% for prophylactic "low” doses and -40% for "high” doses) of the drug mixed into the cement is ever released. The remaining drug gets trapped deep inside the cement. This is wasteful because most of the drug purchased is never released from the cement. As a result, most of the entrapped drug is not released in a concentration sufficient to provide therapeutic benefit.
  • Drug release is not sustained. Drug must be maintained at the site of infection at as a high concentration for as long of a time as possible in order to destroy a bacterial biofilm, which can require 1000 times as much drug
  • bone cement is not degradable. While bone cement is known to be biocompatible, it cannot be used with cementless hip stems and is not re-dosable without an invasive procedure.
  • bone cement is not indicated for use with many cementless hip prosthesis designs.
  • aqueous solution of Applicants' injectable hydrogel composition I overcomes the deficiencies of prior art bone cement.
  • Applicants' hydrogel 1 provides efficient drug release. Because the material eventually dissolves, all of the drug is eventually delivered and utilized. Local delivery provides the highest drug concentration directly where it is needed— at the implant surface.
  • AzTE M12-026L Applicants' hydrogel provides sustained drug release. Throughout the 7-1 0 day period during which the material dissolves, drug is released at a relatively steady rate, which may provide improved performance at preventing or managing prosthetic joint infections.
  • Applicants' hydrogel provides local delivery to the implant surface of cementiess stems without disrupting the quality of fit between the hip prosthesis and the femur.
  • Applicants' hydrogel provides degradability. Previous work by Applicants' and colleagues has shown no difference in immune response from that of native tissue following gel dissolution. The degradability of the material also allows for it to be re-dosable by transcutaneous injection in some cases.
  • FIG. 1 graphically illustrates relative absorbance of 0.25 wt% solutions of Applicants' hydrogel I comprising poly(NIPAAm-cO-DBLA-co-jAAm) with 5.9 mol% DBLA, 2.3 mol% J A Am incubated at 37°C in Phosphate Buffer Solution after 1 day ( ⁇ ), 3 days ( ⁇ ), 7 days ( A ), and 15 days ( ⁇ ).
  • DBLA is dimethyl- butyrolactone aeryiate
  • JAAm is JEFFAMINE M-1000 acrylamide.
  • FIG. 2 shows the LCST of 5 wt% solutions of poly(NIPAAm-co-DBLA-co-JAAm) with 5.9 mol% DBLA, 2.3 mol% JAAm determined by cloud point as a function of time.
  • the LCST for the same polymer without JAAm remains at 18°C for the first 2 weeks.
  • human body temperature is about 37 °C.
  • FIG. 3 shows deswelling of a control polymer 30 wt% po 1 y ( 1 PA A m -co- DBLA) at various times after gelation in excess PBS (pH 7.4) at 7°C.
  • the control copolymer comprises no absence of JAAm. Gels began shrinking rapidly beginning on the first day. These gels dissolve in approximately 20 weeks.
  • FIG. 4 shows swelling and degradation behavior of Applicants' terpolymer I based gel comprising poiy(NIPAAm-co-DBLA-cc>-JAAm) in excess PBS (pH 7.4). Gels retained their initial volume throughout the study and underwent bulk degradation. Gels flow when inverted after 7- 10 days and dissolve completely within 2-3 weeks.
  • FIG. 5 graphically illustrates the mass of vancomycin released from 1 mL gels loaded with 50,000 m icrograms vancomycin HC1 and 1 mL bone cement samples loaded with 142,000 micrograms vancomycin HC1. Release is prolonged and
  • FIG. 6 graphically illustrates an amount of vancomycin released as a fraction of the drug loaded. Most of the drug that is loaded into bone cement is not released whereas Applicants' injectable and degradable terpolymer I based gels comprising po 1 v ( I PA A m -co -D B I . A -co- J A Am ) release nearly all of the drug loaded into them within 8 days.
  • FIG. 7 graphically illustrates a fraction of loaded vancomycin released from Applicants' injectable and degradable terpolymer I based gels comprising poly(NIPAAni-co-DBLA-co-JAAm) gels loaded with either 50 mg or 5 mg per gel. Some vancomycin is insoluble when loaded into the polymer solution at 50 mg/mL. The similarity between these curves indicates that the polymer, as opposed to the drug solubility, is primarily responsible for controlling the rate of drug release.
  • FIG. 8 summarizes Applicants' method to deliver a medicament to an injection site within the body of an animal, including a human.
  • the injection site comprises the surface of an bone implant.
  • the method provides a medicament and a first hydrogel comprising a first LCST less than the body temperature of the subject animal.
  • body temperature for a human is about 37 °C.
  • the first hydrogel of step 810 comprises a LCST less than about 37 °C.
  • Applicants mean a material selected from the group consisting of a Nucleic acid, a Protein (including growth factors, bone morphogenetic proteins), a Polypeptide, a Contrast agent for imaging, an Anesthetic, an Antineoplastic agent, an Antifungal, an Anti-inflammatory drug (steroids, non-steroidal antiinflammatory drugs (NSAIDs), and an Antibiotic.
  • the Antibiotic comprises one or more of Aminoglycosides, including gentamicin, amikacin, and tobramycin. Cephalosporins including eefazolin, Vancomycin, and Rifampin
  • the first hydrogel of step 810 comprises a polymeric material comprising a backbone formed from polymerization of one or more
  • hydrolyzab!c linkages and a monomer comprising a water soluble polymer moiety attached thereto.
  • the first hydrogel of block 810 comprises Applicants' hydrogel I.
  • the first hydrogel of block 810 comprises Applicant's hydrogel formed from N-isopropylacrylamide, J EFFAMI E M-1000 acrylamide (JAAm). and acryloyloxy- ,P-dimethyl-Y-butyroiaetone.
  • the first hydrogel of step 810 comprises Applicant's hydrogel comprising poly( lPAAm-co-DBLA-c -JAAm) with 5.9 moi% DBLA and 2.3 mol% JAAm.
  • an aqueous solution of the medicament and the first hydrogel of block 810 is injected into a selected animal at a temperature less than the first LCST.
  • the injection site comprises a tissue space wherein a subsequently formed gel will substantially completely fill that tissue space.
  • the first hydrogel of block 810 is utilized in conjunction with implantation of an artificial joint. In certain of these embodiments, the injection of block 820 is performed after implantation such that the injected hydrogel is disposed adj acent a surface of the implanted artificial joint.
  • the hydrogel of block 810 is coated onto a surface of an artificial joint prior to implantation.
  • the "injection" of block 820 comprises implantation of the artificial joint comprising a surface coated with the first hydrogel of block 810.
  • the first hydrogel of block 810 injected into the body of an animal in block. 820 is warmed in vivo to a temperature greater than the first LCST.
  • the warmthing of block 830 is performed by the body heat of the animal.
  • the warming of block 830 is performed by disposing a heating object, such as for example and without limitation, a heat lamp, a heating pad, hot compress, and the like, directed in near proximity to the injection site.
  • the water-insoluble eel forms in vivo a water-insoluble eel.
  • the water-insoluble eel forms in vivo a water-insoluble eel.
  • AzTE M 12-026L insoluble gei of block 840 is formed in, and substantially fills, a tissue space.
  • the water-insoluble gel of block 840 is disposed on, and in near vicinity to, a surface of a joint implant.
  • the release of medicament is sustained over time.
  • the release is approximately proportional to the square root of time over the first 60% of release, with a slower rate of release thereafter.
  • the first hydro g l of block 810 which was injected in block 820 is chemically modified to form a second hydrogel having a second LCST, wherein the second LCST is greater than body temperature.
  • the second LCST is greater than body temperature.
  • the pendent ester moieties of the plurality of repeat units IV are hydrolyzed in vivo to convert first terpoiymer I injected in block 820 and gelled in block 840 to a second terpoiymer XXII, wherein R9 comprises a pendent hydroxy! group or a pendent carboxylic acid group resulting from a hydrolysis of an acid moiety or an anhydride moiety, respectively, in pendent group R8.
  • R6 comprises a substituted buiyroiactone motety and R8 is an ester linkage
  • the pendent substituted buiyroiactone moieties of the plurality of repeat units IV are hydrolyzed in vivo to convert first terpolymer I injected in block 820 and gelled in block 840 to a second terpolymer XXI II.
  • R9 comprises a carboxylic acid moiety.
  • the first hydrogel of block 810 is converted into a second hydrogel XXII / XXIII that is water soluble at body temperature.
  • the water soluble second hydrogel dissolves in body fluids.
  • step 880 the second hydrogel of step 870 is excreted from the body.
  • the first hydrogel is warmed to a temperature greater than its LCST, and a water-insoluble gel is formed. The medicament is released over time from the water-insoluble gel. Thereafter, the first hydrogel is converted in vivo into a second
  • J AzTE M12-026L hydrogel having a LCST greater than body temperature. This second hydrogel is water soluble, and is carried by the animal's circulatory system to its kidneys. The second hydrogel is then excreted from the body.

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  • Engineering & Computer Science (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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EP12840669.1A 2011-10-12 2012-10-12 In-situ-formendes hydrogel und verfahren zu seiner verwendung Withdrawn EP2765991A4 (de)

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US10265439B2 (en) 2015-09-03 2019-04-23 Arizona Board Of Regents On Behalf Of Arizona State University Injectable cell-laden biohybrid hydrogels for cardiac regeneration and related applications
EP3541442B1 (de) * 2016-11-16 2022-01-19 Persica Pharmaceuticals Ltd. Antibiotische formulierungen für rückenschmerzen im unteren rückenbereich
US11173210B2 (en) 2017-10-24 2021-11-16 Sonoran Biosciences, Inc. Temperature-responsive degradable hydrogels
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WO2013056170A1 (en) 2013-04-18
US20180153956A1 (en) 2018-06-07

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